Mutant huntingtin interacts with {beta}-tubulin and disrupts vesicular transport and insulin secretion.

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Abstract

Huntington's disease is a severe progressive neurodegenerative disorder caused by a CAG-expansion in the IT15 gene, which encodes huntingtin. The disease primarily affects the neostriatum and cerebral cortex and also associates with increased incidence of diabetes. Here, we show that mutant huntingtin disrupts intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin. We demonstrate that mutant huntingtin impairs glucose-stimulated insulin secretion in insulin-producing beta-cells, without altering stored levels of insulin. Using VSVG-YFP, we show that mutant huntingtin retards post-Golgi transport. Moreover, we demonstrate that the speed of insulin vesicle trafficking is reduced. Using immunoprecipitation of mutant and wild-type huntingtin in combination with mass spectrometry, we reveal an enhanced and aberrant interaction between mutant huntingtin and beta-tubulin, implying the underlying mechanism of impaired intracellular transport. Thus, our findings have revealed a novel pathogenetic process by which mutant huntingtin may disrupt hormone exocytosis from beta-cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein.

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  • Medical Genetics
Original languageEnglish
Pages (from-to)3942-3954
JournalHuman Molecular Genetics
Volume18
Issue number20
Publication statusPublished - 2009
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Metabolism (013212001), Islet cell physiology (013212142), Translational Neuroendocrinology (013210010), Connective Tissue Biology (013230151), Neuronal Survival (013212041), Insulin Signal Transduction (013212014), Department of Experimental Medical Science (013210000)